Targeted drug development in acute myeloid leukemia and diffuse large B cell lymphoma

Sarit Assouline

Hôpital général juif

Résumé du projet

My research centers on the clinical development of new treatments for leukemia and lymphoma guided by basic science research.

To date, I have completed 2 clinical trials which have looked at whether ribavirin can target a protein, eIF4E, which is increased in some forms of leukemia. These two trials have shown that ribavirin can work but they have also shown a mechanism by which the leukemia is resistant. This mechanism is mediated by the sonic hedgehog pathway and can be blocked by vismodegib, a drug that blocks one element of the pathway. I am therefore embarking on a third clinical trial of ribavirin and vismodegib to see if this approach works in patients with acute myeloid leukemia.

I have also completed a clinical trial in relapsed diffuse large B cell lymphoma (DLBCL) in which patients were treated with panobinostat, a histone deacetylase inhibitor. Thirty percent of patients responded in the trial and some had very durable responses. During this trial, we noted that some patients, although not responding, had a change in their tumor gene expression that could make them more sensitive to proteasome inhibitors. We therefore tested in cell lines and mouse models whether this phenomenon could be reproduced. In fact, in the lab, the same findings occurred and the cell lines were indeed exquisitely sensitive to ixazomib, an inhibitor of the proteasome. I am therefore planning a clinical trial combining panobinostat and ixazomib in order to increase responses in patients with DLBCL.

My success in these projects has rested on the infrastructure and networks that I have established. These in turn have allowed for the innovative approaches that I describe.